Differential transport of Influenza A neuraminidase signal anchor peptides to the plasma membrane

Ernst, Andreas; Zacherl, Sonja; Herrmann, Alexia; Hacke, Moritz; Nickel, Walter; Wieland, Felix; Brügger, Britta

doi:10.1016/j.febslet.2013.03.019

Cited by 13 publications

(11 citation statements)

References 23 publications

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“…This position is located in the transmembrane domain and is not likely to affect the structure of the NA pocket. Such a polymorphism has already been observed [28] but not analyzed functionally. This mutation may modify monomers in terms of their anchorage or interactions, with repercussions on NA expression on the virus surface.…”

Section: Discussionmentioning

confidence: 90%

Functional Balance between the Hemagglutinin and Neuraminidase of Influenza A(H1N1)pdm09 HA D222 Variants

et al. 2014

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D222G/N substitutions in A(H1N1)pdm09 hemagglutinin may be associated with increased binding of viruses causing low respiratory tract infections and human pathogenesis. We assessed the impact of such substitutions on the balance between hemagglutinin binding and neuraminidase cleavage, viral growth and in vivo virulence.Seven viruses with differing polymorphisms at codon 222 (2 with D, 3 G, 1 N and 1 E) were isolated from patients and characterized with regards hemagglutinin binding affinity (Kd) to α-2,6 sialic acid (SAα-2,6) and SAα-2,3 and neuraminidase enzymatic properties (Km, Ki and Vmax). The hemagglutination assay was used to quantitatively assess the balance between hemagglutinin binding and neuraminidase cleavage. Viral growth properties were compared in vitro in MDCK-SIAT1 cells and in vivo in BALB/c mice. Compared with D222 variants, the binding affinity of G222 variants was greater for SAα-2,3 and lower for SAα-2,6, whereas that of both E222 and N222 variants was greater for both SAα-2,3 and SAα-2,6. Mean neuraminidase activity of D222 variants (16.0 nmol/h/106) was higher than that of G222 (1.7 nmol/h/106 viruses) and E/N222 variants (4.4 nmol/h/106 viruses). The hemagglutination assay demonstrated a deviation from functional balance by E222 and N222 variants that displayed strong hemagglutinin binding but weak neuraminidase activity. This deviation impaired viral growth in MDCK-SIAT1 cells but not infectivity in mice. All strains but one exhibited low infectious dose in mice (MID50) and replicated to high titers in the lung; this D222 strain exhibited a ten-fold higher MID50 and replicated to low titers. Hemagglutinin-neuraminidase balance status had a greater impact on viral replication than hemagglutinin affinity strength, at least in vitro, thus emphasizing the importance of an optimal balance for influenza virus fitness. The mouse model is effective in assessing binding to SAα-2,3 but cannot differentiate SAα-2,3- from SAα-2,6- preference, nor estimate the hemagglutinin-neuraminidase balance in A(H1N1)pdm09 strains.

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Section: Discussionmentioning

confidence: 90%

Functional Balance between the Hemagglutinin and Neuraminidase of Influenza A(H1N1)pdm09 HA D222 Variants

et al. 2014

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“…In N1, three leading sites 59, 386 and 388 (70, 390, and 392 in N2 numbering), and trailing site 434, undergo host-specific position-specific glycosylation, likely affecting enzymatic activity of NA [39]. Leading sites 6 and 14 and trailing site 15 are located in the transmembrane domain, which affects viral sialidase activity through its effect on NA tetramer assembly and transport to the membrane [40,41]. Leading site 149 and trailing sites 83, 275, 267 and 287 (274, 266, and 286 in N2 numbering) affect sialic acid binding; mutations at sites 267 and 275 were also shown to affect resistance to oseltamivir, including the mutation at site 275 which gave rise to the common oseltamivir-resistant H1N1 subtype.…”

Section: Resultsmentioning

confidence: 99%

“…For example, sites in the signal peptide of HA appear to occasionally interact with sites in the transmembrane domain of NA, e.g., site H1-16 forms a putatively epistatic pair with site N1-15 (Table S6). These types of mutations likely affect the efficiency of membrane localization of the respective surface proteins [40], and mutations in the transmembrance domain may also influence NA activity through their effect on tetramer assembly [41].…”

Section: Discussionmentioning

confidence: 99%

Coordinated Evolution of Influenza A Surface Proteins

Neverov

Kryazhimskiy

Plotkin

et al. 2014

Preprint

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The surface proteins hemagglutinin (HA) and neuraminidase (NA) of human influenza A virus evolve under selection pressures to escape adaptive immune responses and antiviral drug treatments. In addition to these external selection pressures, some mutations in HA are known to affect the adaptive landscape of NA, and vice versa, because these two proteins are physiologically interlinked. However, the extent to which evolution of one protein affects the evolution of the other one is unknown. Here we develop a novel phylogenetic method for detecting the signatures of such genetic interactions between mutations in different genes -that is, inter-gene epistasis. Using this method, we show that influenza surface proteins evolve in a coordinated way, with mutations in HA affecting subsequent spread of mutations in NA and vice versa, at many sites. Of particular interest is our finding that the oseltamivir-resistance mutations in NA in subtype H1N1 were likely facilitated by prior mutations in HA. Our results illustrate that the adaptive landscape of a viral protein is remarkably sensitive to its genomic context and, more generally, that the evolution of any single protein must be understood within the context of the entire evolving genome. Author SummaryThe fitness of an organism depends on the coordinated function of many genes. Thus, how a mutation in one gene affects fitness often depends on what mutations are present in other genes. This dependence is called "genetic interaction" or "epistasis". The prevalence and type of such interactions are not well understood. Epistasis can be inferred from timeseries sequencing data when a mutation in one gene is observed to facilitate the spread of a mutation in another gene. However, the situation is much more complicated when new combinations of genes are formed by processes such as recombination or reassortment. In such cases, deducing the time and order of genetic changes is difficult. Here, we devise a method to infer pairs of mutations in different genes which closely follow one another in the presence of reassortment. We apply it to evolution of two surface proteins of influenza A virus, hemagglutinin and neuraminidase, which are important targets for the human immune system and drugs. We show that mutations in one of these proteins are often facilitated by prior mutations, or compensated by subsequent mutations, in the other protein. In particular, drug-resistance mutations in neuraminidase were likely made possible by prior mutation in hemagglutinin. Knowledge of such interactions is necessary to fully understand and predict evolution.

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“…The first 41 N-terminal amino acids of the influenza virus NA, a type II membrane protein with an uncleaved signal peptide, allow translocation and intracellular transport of transplanted sequences (21). Therefore, this sequence containing the signal peptide plus the following linker region (14 amino acids) was used to replace the signal peptide of Gp3.…”

Section: Resultsmentioning

confidence: 99%

Co-translational Processing of Glycoprotein 3 from Equine Arteritis Virus

Matczuk

Kunec

Veit

2013

Journal of Biological Chemistry

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Background: N-Glycosylation and signal peptide cleavage are co-translational modifications of membrane proteins. Results: Attachment of carbohydrates adjacent to a potentially cleavable signal peptide inhibits its processing in a glycoprotein from an arterivirus. Conclusion: Glycosylation occurs prior to signal peptide cleavage, contrary to other proteins analyzed in this regard. Significance: A similar processing scheme might exist for some cellular proteins.

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Differential transport of Influenza A neuraminidase signal anchor peptides to the plasma membrane

Cited by 13 publications

References 23 publications

Functional Balance between the Hemagglutinin and Neuraminidase of Influenza A(H1N1)pdm09 HA D222 Variants

Functional Balance between the Hemagglutinin and Neuraminidase of Influenza A(H1N1)pdm09 HA D222 Variants

Coordinated Evolution of Influenza A Surface Proteins

Co-translational Processing of Glycoprotein 3 from Equine Arteritis Virus

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